2. Academic Validation
  3. Structure-Guided Design of Potent and Selective Covalent Inhibitors Targeting the SARS-CoV-2 Papain-like Protease

Structure-Guided Design of Potent and Selective Covalent Inhibitors Targeting the SARS-CoV-2 Papain-like Protease

  • J Med Chem. 2026 Feb 12;69(3):2197-2214. doi: 10.1021/acs.jmedchem.5c01973.
Mona Sharafi 1 2,  Wei Pin Teh 1 2,  Jeremy Green 3,  Paul S Charifson 3,  Jinhua Wang 1 2,  Orville A Pemberton 4,  Amanda M Nevins 4,  Ming Lye 2,  Xiaoxi Liu 1 2,  Anthony C Varca 1 2,  Callum D Owen 5,  Kimberley Morsheimer 5 4,  Alan Wacquiez 6,  Christpher Dawson 3,  Christopher Steuber 3,  Jennifer Smith 3,  Nicholas M Girardi 1 2,  Robert S Magin 1 2,  Jarrod A Marto 1 7,  Mohsan Saeed 6,  Rob A Davey 5,  David Hardee 4,  Teresa I Ng 4,  Mark N Namchuk 2 3,  Sara J Buhrlage 1 2
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, United States.
  • 3 Drug Discovery Sciences Core, Blavatinik Institute, Harvard Medical School, Boston, Massachusetts 02115, United States.
  • 4 Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
  • 5 National Emerging Infectious Diseases Laboratories, Department of Virology, Immunology, and Microbiology, Chobanian and Avedisian School of Medicine, Boston University, Boston, Massachusetts 02118, United States.
  • 6 National Emerging Infectious Diseases Laboratories, Department of Biochemistry and Cell Biology, Chobanian and Avedisian School of Medicine, Boston University, Boston, Massachusetts 02118, United States.
  • 7 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02215, United States.
PMID: 41557701 DOI: 10.1021/acs.jmedchem.5c01973
Abstract

The COVID-19 pandemic led to numerous initiatives to create Antiviral medications and vaccines for the treatment and prevention of infections. However, the need remains for new therapies with distinct mechanisms of action from current treatment of COVID-19 infections as well as for future pandemic preparedness. SARS-CoV-2 papain-like protease (PLpro) is a cysteine protease that cleaves the viral polyprotein and possesses deubiquitylase (DUB) and deISGylase activity that can act on host proteins. Here, we report the structure-guided development of covalent inhibitors of SARS-CoV-2 Plpro that possess low nanomolar to subnanomolar Antiviral activity in cell assays and inhibit viral replication in a mouse model of SARS-CoV-2 Infection. The most potent inhibitors contain N-propargylamide electrophiles, a relatively inert warhead not typically featured in covalent Protease Inhibitors. These findings provide a foundation for further discovery and optimization of covalent PLpro inhibitors that could lead to future Antiviral therapeutics.

Figures
Products